Cancer Immunology, Immunotherapy

, Volume 63, Issue 2, pp 111–119 | Cite as

Critical role of spatial interaction between CD8+ and Foxp3+ cells in human gastric cancer: the distance matters

  • Anita Feichtenbeiner
  • Matthias Haas
  • Maike Büttner
  • Gerhard G. Grabenbauer
  • Rainer Fietkau
  • Luitpold V. DistelEmail author
Original Article



In various cancer types, an abundance of FoxP3+ regulatory T cells (Treg) has been associated with an unfavorable outcome. Yet, the role of Treg on cancer immunity has been shown to be complex. In single cell marker technique, other tumor-infiltrating lymphocytes (TILs) such as cytotoxic CD8+ T cells (CTL) also influenced prognosis. This study for the first time investigates the concurrent spatial distribution pattern of CD8+ and FoxP3+ TILs and their prognostic impact in human gastric cancer.

Materials and methods

Tumor tissue microarrays of 50 patients with surgically treated adenocarcinoma of the cardia were studied. An immunohistochemical double staining of CD8+ and FoxP3+ TILs was performed. Cell counts and cell-to-cell distances in tumor epithelium and stroma were evaluated with image-processing software. Metastasis-free survival, no-evidence-of-disease survival, and overall survival were investigated (mean follow-up time 6.9 years).


High intraepithelial infiltration of CD8+ and FoxP3+ TIL was associated with the improved 10-year metastasis-free survival (83 vs. 54 %, p = 0.04 and 85 vs. 59 %, p = 0.09, respectively). Considering cell-to-cell distance and comparing patients with functional (30–110 μm) versus nonfunctional distances of CD8+ and FoxP3+ TILs, 10-year survival rates differed between 89 and 55 % (p = 0.009), respectively.


Prognostic influence of tumor-infiltrating immune cells in gastric cancer critically depends on their cell-to-cell distance. FoxP3+ TILs must be located within a distance between 30 and 110 μm of CD8+ T cells to positively impact on prognosis.


Regulatory T cells Cytotoxic T cells Tumor-infiltrating lymphocytes Gastric cancer Cancer immunology Immune evasion 



We thank Christa Winkelmann for excellent technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

262_2013_1491_MOESM1_ESM.pdf (3.9 mb)
Supplementary material 1 (PDF 4023 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Anita Feichtenbeiner
    • 1
  • Matthias Haas
    • 3
  • Maike Büttner
    • 2
  • Gerhard G. Grabenbauer
    • 1
  • Rainer Fietkau
    • 1
  • Luitpold V. Distel
    • 1
    Email author
  1. 1.Department of Radiation Oncology of the University HospitalsFriedrich-Alexander-University of Erlangen-NürnbergErlangenGermany
  2. 2.Institute of Pathology of the University HospitalsFriedrich-Alexander-University of Erlangen-NürnbergErlangenGermany
  3. 3.Department of RadiologyCharité UniversitätsmedizinBerlinGermany

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